1-(3-C-Ethynyl-β-D-ribopentofuranosyl)cytosine (ECyd, represented by the following formula) is a novel antimetabolite having a structure in which the 3′-β-position of the ribose of cytidine is substituted by an ethynyl group.

ECyd is a cytidine analogue which was first synthesized in Japan. Differing from a pyrimidine derivative (5-FU) or a deoxycytidine derivative (gemcitabine), which are antitumor agents generally employed in the clinical settings, ECyd weakly acts on DNA and mainly inhibits RNA synthesis. Specifically, in a proposed mechanism, ECyd is phosphorylated by intracellular uridine/cytidine kinase, to thereby form a triphosphate (ECTP), which inhibits RNA polymerases I, II, and III, leading relevant cells to death.
Many antitumor agents which are generally employed in the clinical settings and which work based on DNA synthesis inhibition as a main action exhibit the inhibitory effect in an S-phase. Tumor cells employed in animal tests generally exhibit relatively fast proliferation. However, studies have revealed that, in the clinical settings, tumor cells proliferate at a slow rate, and a small number of the cells are in the S-phase. Since, differing from DNA synthesis inhibiting agents, the antitumor effect of ECyd based on RNA synthesis inhibitory action is not affected by the cell cycle of tumor cells, ECyd is thought to serve as a clinically useful antitumor agent, which differs from DNA synthesis inhibiting agents generally employed in the clinical settings.
ECyd exhibits a potent antitumor effect on a wide range of tumors (Non-Patent Documents 1 and 2). In a tumor inhibition test employing animal models, ECyd was found to exhibit potent antitumor effect on a variety of human-derived tumor strains through rapid intravenous injection (i.e., bolus intravenous injection) once a week for two weeks (Non-Patent Document 3). In the animal models, virtually no significant adverse effects were observed at an effective ECyd dose which provides antitumor effect and, therefore, ECyd is a promising candidate for a useful agent in the clinical setting.
Meanwhile, a clinical phase I test of a cancer treatment agent containing ECyd as an active ingredient was performed in the United States. In the test, when ECyd was administered through rapid intravenous injection with a regimen of administration once every three weeks or a regimen of administration once a week for three weeks and a rest period for one week, a sufficient blood ECyd level was obtained. The test showed that ECyd has a tumor growth inhibitory action with respect to some multiple-cancer patients who cannot be treated by a conventional drug.
However, peripheral neurotoxicity was observed as a dose-limiting toxicity, rendering difficult a further increase in dose of ECyd for evaluation thereof as an antitumor agent and continuous administration of ECyd. Thus, the cancer therapeutic effect of ECyd is unsatisfactory in the clinical setting (Non-Patent Documents 4 and 5).
Non-Patent Document 1: J. Med. Chem., 39, 5005-5011, 1996
Non-Patent Document 2: Oncol. Rep., 3, 1029-1034, 1996
Non-Patent Document 3: Jpn. J. Cancer Res., 92, 343-351, 2001
Non-Patent Document 4: EORTC-NCI-AACR Symposium, Abs. 67A, 2002
Non-Patent Document 5: EORTC-NCI-AACR Symposium, Abs. 364, 2002